This project is predicated upon our preliminary studies that show that typhus rickettsiae cause human endothelial cells (EC) to secrete increased amounts of prostaglandins I2 (PGI2) and E2 (PGE2). The purpose of this project is to determine if rickettsiae (R) elicit a similar phenomenom during the typhus toxic reaction in rodents. These studies will be extended to determine if R:granulocyte interactions result in increased secretion of another set of arachidonic acid (AA) derivatives - the leukotrienes (LT). These studies will allow us to not only examine the role AA derivatives play in generation of the typhus toxic reaction, but, when correlated with our ongoing studies of R:human cell interactions, should help us determine if rickettsial toxic reactions in rodents can serve as a model for events occuring during acute typhus. Mouse macrophages (from various sources) and PMN will be exposed to high multiplicities of R, and target cell secretion of PG's and LT's will be assessed by radioimmunoassay. R effects on mouse-derived EC will also be determined. Inhibitor studies will examine the mechanism of target cell PG and LT response. Next, mice will be injected with a lethal dose of R, and plasma levels of PG and LT will be monitored. Finally, mice will be administered inhibitors of PG and LT synthesis and inhibitor effects on (i) R LD50 for mice, (ii) increased vascular permeability, and (iii) plasma PG and LT levels will be determined. This combination of in vitro and in vivo studies will allow us to characterize participation of AA derivatives in development of the typhus toxic reaction. If the molecular pathogenesis of this phenomenom is similar to that of certain events occuring during acute typhus, this may allow development of the mouse as a model for testing (i) protective efficacy of antibodies directed against rickettsial epitopes (vaccine development), and (ii) symptom-directed treatments for typhus.